Intensive Protocol Research Articles

Hepatitis B Reactivation without Hepatitis Is a Common Event in Adolescent/Adult Patients of Acute Lymphoblastic Leukemia with Occult Hepatitis B (OHBI) Treated on Pediatric Protocols and Warrants Prophylactic Antivirals: A Prospective Cohort Study

Introduction: Patients with occult Hepatitis B infection(OHBI) (HBsAg negative but HBcIgG &/or anti-HBs positive in the absence of immunization) are at an increased risk of Hepatitis B(HBV) reactivation while on and after chemotherapy. It can present over a spectrum ranging from asymptomatic or mild transaminitis to fatal hepatitis, affect the dose intensity of chemotherapy and compromise outcomes. The reported risk of reactivation is variable (1-24%, Yeo, 2009), and depends on the type of therapy and the method used to detect reactivation. Antiviral prophylaxis is recommended in patients with OHBI who are treated with antiCD20 monoclonal antibodies and those who undergo allogeneic stem-cell transplant, however this has not been evaluated in patients treated on pediatric-inspired ALL protocols comprising of several immunosuppressive drugs.. Methods: This was a prospective longitudinal cohort study conducted at a single tertiary care center in India between October 2017 to July 2021 (CTRI/2017/01/007747). The primary objective was to study the incidence of HBV reactivation in patients with OHBI on ALL protocol, and secondary objectives were to study the incidence of OHBI, HBV related hepatitis and its impact on chemotherapy intensity. Newly diagnosed patients with ALL/LBL, aged ≥15 years were screened for the presence of OHBI. Patients with OHBI were considered for enrollment into the prospective part of the study if they were treated on intense protocol (modified BFM-90 ALL protocol), had normal liver function tests, and no co-infection with HCV, HIV or history of HBV vaccination. Liver functions were monitored twice weekly during the induction/reinduction phase, prior to the early and delayed intensification and once every 2-3 months during the maintenance phase. HBV DNA copies by quantitative PCR (threshold for detection 20 units/ml), were measured at baseline, week 4, week 8, week 20, 32, week 48, completion of maintenance and every 3-6 months for 1 year. If a patient developed hepatitis, serum was collected for HBV DNA levels, HBsAg, HB core IgM antibody, IgM HAV antibody, IgM HEV, HCV and CMV DNA levels. HBV reactivation was defined as- either increase in serum HBV DNA level to more than 1 log higher than that of baseline or any copy numbers if it was negative at baseline. Seventy five patients with OHBI were to be studied to detect a true incidence of >10% HBV reactivation at a one-sided significance level of 5% and 90% power (Fleming's design) Results: A total of 566 patients were screened for the study, and 172(30.4% (95% C.I. (26.6-34.4)) patients were diagnosed with OHBI. 74 patients were enrolled in the prospective part of the study (Fig 1). The baseline characteristics of the study population are summarized in Table 1. HBV DNA was detectable at baseline in only 2(2.3%) patients. 51 patients (68.9%) completed all phases of treatment. The median follow-up was 21.6 months (range 0.03-53.5 months). A total of 402 HBV DNA tests were done in this cohort with an average of 5 tests per patient. HBV reactivation occurred in 5 patients ((6.7% 95% C.I.(1.03-12.47)), none of these patients developed hepatitis during HBV reactivation. In all the patients, reactivation occurred during the maintenance phase. All of these patients were started on antivirals (Entecavir). Overall 15(20.3%) patients developed hepatitis during the study period and CMV viremia was the cause for hepatitis in 4(26.7%) patients and HCV infection was the cause in 1 (6.6%) patient. Median AST, ALT during the episodes of hepatitis were 363 and 459 respectively (range AST 150-3490, range ALT 218-1950). Two(2.7%) patients had a delay in administration of chemotherapy due to hepatitis and median duration of delay was 21 days (range 18-24). Conclusion: We conclude that the risk of HBV reactivation is significant in adolescent/adult ALL patients with OHBI treated on pediatric inspired ALL protocols. HBV related hepatitis is a late event, and monitoring with liver function tests alone is not sufficient. The use of prophylactic antivirals is justified in patients with ALL.

Different Epidemiology and Characteristics of Invasive Pulmonary Aspergillosis in Acute Lymphoid Leukemia in Comparison with AML: Results of a Prospective Multicentric Observational Study of the Rete Ematologica Lombarda (REL)

Introduction. Invasive pulmonary aspergillosis (IPA) still affects the outcome of acute leukemia (AL) patients (pts). Although this aspect is better defined in acute myeloid leukemia (AML) ( Candoni et al, Mycoses 2020), some reports show a dismal impact also in acute lymphoid leukemia (ALL) ( Cattaneo et al, Leuk Lymphoma 2019). However, data concerning the epidemiology of IPA in adult ALL patients, as well as the best antifungal prophylaxis strategy, are still lacking. Therefore, to describe the incidence of IPA in AL pts and their clinical characteristics, as well as the predisposing factors, we carried out a prospective multicentric observational study within the Rete Ematologica Lombarda (REL). Methods. All consecutive AL patients diagnosed during a 3-year period and treated with curative intent were recorded. Diagnosis of IPA was defined according to EORTC/MSG criteria ( Donnelly et al, Clin Infect Dis 2020). Data concerning age, gender, AL type, chemotherapy (cht) received, complete remission (CR) achievement, antifungal prophylaxis, duration of neutropenia and 30-day mortality were collected. Patient's characteristics were analysed by standard descriptive statistics. The Student's t-test was used to compare continuous values; the Fisher's exact test was used to compare differences in percentage. P values below 0.05 were considered statistically significant. Results. Between 2018 and 2020, 207 AL pts (AML: 165, ALL: 42) were evaluated in five Hospitals participating to the REL. Median age of the whole cohort was 58y, and M/F ratio 112/95. After induction treatment, CR was achieved in 153 of the 200 evaluable pts (76.5%), more frequently in ALL (38/42, 90.5%) than in AML pts (115/158, 72.8%) (p=0.0146). During induction cht, proven/probable (p/p) and possible (poss) IPA were diagnosed in 32/207 pts (15.4%), equally divided in p/p and poss (16 each, 7.7%). P/p IPA were more frequent in ALL than in AML (ALL: 7/42, 16.6% vs AML: 9/165, 5.4%; p= 0.0235); similarly, considering also poss IPA, incidence was higher, even if not significantly (9/42, 21.4% vs 23/165, 13.9%; p=0.2374). Among ALL pts, IPA was more frequent in pts not achieving CR (2/4, 50%) than CR pts (7/38, 18%), whereas in AML CR achievement did not influence IPA frequency (CR group: 15/115, 13%; no CR group: 7/43: 16.5%). ALL pts were uniformly treated with pediatric-like protocols; in AML pts no statistically significant differences in IPA incidence were observed according to cht received (3+7/like: 13/81, 16%; 3+7+midostaurin: 2/27, 7.4%; FLAG-Ida: 3/21, 14.3%; CPX-351: 4/19, 21%). Antimould prophylaxis was protective against IPA in 202 evaluable pts (Yes: 22/171, 12.9%; No: 10/31, 32.3%, p=0.0134). Among ALL pts only 1 out of 15 (6.7%) receiving antimould prophylaxis developed IPA, as compared to 8/27 (29.6%) of those not receiving antimould prophylaxis (p=0.1235). All but two AML pts developing IPA were on posaconazole prophylaxis. Both mean age and duration of neutropenia were significantly lower in ALL than in AML pts (46.02y vs 57.75y, p<0.0001 and 16.66d vs27.96d, p<0.0001); however, an impact of mean duration of neutropenia on IPA incidence was observed only in ALL pts (IPA group: 24.38d; no IPA group: 14.79d, p=0.0359). Only 2 AML pts died at 30d: 1 (3.1%) out of 32 pts with IPA and 1 (0.6%) out of 175 pts without. No early death was observed in ALL pts. Table 1 summarizes the clinical characteristics of AL pts in relation to IPA. Conclusions. Despite younger age, shorter duration of neutropenia and higher percentage of CR achievement, IPA, particularly p/p, was more frequently observed in ALL pts than AML during induction cht. High dose induction cht seems to have no impact in IPA incidence in AML pts. On the other hand, intensive cht ALL protocols, including high doses of dexamethasone, could have a role in IPA development, as well as the lack of antimould prophylaxis, which is confirmed as a predictive factor for IPA. Therefore, studies with antimould agents as prophylaxis against aspergillosis in ALL pts during inductions would be desirable.

Tyrosine Kinase Inhibitor (TKI) Discontinuation in Non-Allografted Ph+ Acute Lymphoblastic Leukemia Patients, a Campus ALL Real-Life Study

Introduction. Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients are commonly treated with tyrosine kinase inhibitors (TKI) in combination with either steroids, chemotherapy and more recently also immunotherapy. In the past, allogeneic transplant (SCT) was considered the only curative option; however, with the introduction of more potent TKIs as well as immunotherapy this milestone is nowadays debated, mostly for patients who achieve a molecular response. Moreover, as in chronic myeloid leukemia (CML), it is becoming relevant to understand if patients may over time discontinue TKI treatment. For this purpose, it is pivotal to report the outcome of Ph+ ALL patients who, for any reason, stopped TKI treatment. Patients and Methods. Forty-seven adult Ph+ ALL patients treated since 1 January 2000, and who did not undergo a SCT, were retrospectively collected from 12 Italian centers participating to the Campus ALL network. Their treatment plan included a TKI +/- chemotherapy according to the center current practice and/or according to the ongoing national trial they were enrolled in. The median age was 63 years (20-84), 20 patients (43%) were males, 30 patients harbored a p190 transcript, 15 a p210 transcript and 2 had both transcripts. Twenty-six patients were treated within a trial, while 21 were off-protocol. For 32 patients, induction was based only on a TKI plus steroids, whereas the remaining 15 received a combination of a TKI plus chemotherapy (in 3 cases high intensity protocols such as the NILG (Northern Italian Leukemia Group) and HCVAD regimens, in 12 low dose chemotherapy). The reasons not to transplant patients were: donor unavailability (5), clinical decision, mainly due to age/unfitness (30), patient's refusal (4), and achievement of a molecular response (i.e. at least BCR-ABL/ABL ≤0.01%) (8). The median follow-up was 60 months, with a median overall survival (OS) not reached at the last follow-up and a median disease-free survival (DFS) of 12 years. At the last follow-up, 12/47 patients had experienced a relapse. At the end of the induction (i.e. after 3 months, at a median of +82 days, from treatment initiation), 27 patients had achieved a molecular response. Overall. a molecular response was obtained in 40/46 pts (data not available for 1 case) after a median of 5 month, and was associated with a significantly lower hazard of disease recurrence (HR=0.057, 95% CI: 0.006-0.51, p=0.011) after adjusting for gender, fusion protein, association with chemotherapy, CMR at 3 months. Results. TKI treatment was discontinued in 14 of the 47 patients evaluated. The reasons for discontinuation were either toxicity (6) or clinical/patient decision (8). Eight patients harbored a p190 transcript, 5 a p210 transcript and 1 carried both. At the time of discontinuation, the median age was 75 years (23-87) and patients had been on a TKI for a median of 57.5 months (8-160) prior to stopping treatment. For these cases, the median WBC at diagnosis were 8.6 x 10 9/l (2.1-306 x 10 9/l). In 7 patients the first TKI used was imatinib, in 3 dasatinib, in 3 ponatinib and in 1 nilotinib. All patients but 1 had achieved a molecular response before stopping treatment; the only patient who never achieved a molecular response prior to discontinuing the TKI had a rapid relapse (1 month). At the last follow-up, 9 cases were still in treatment-free remission (TFR), whereas 5 eventually relapsed after 1, 1, 4, 14 and 30 months, respectively. Re-challenge with a TKI led to a hematological and molecular response in 3 of the 5 patients. The remaining 2 patients, who had been previously heavily treated and whose TFR was of only 1 month, received salvage standard chemotherapy but eventually died from ALL progression. The median time of TFR for the entire cohort of 14 patients was 20.5 months (1-82). When considering only the 9 patients who remain off treatment, the median time of TFR was 29.5 months (7-82) (Table 1, Figure 1). Conclusions. We report the outcome of 14 Ph+ ALL patients who discontinued TKI treatment due to various reasons. Nine of them are still on TFR after more than 2 years at the last follow-up, reinforcing the concept that a TFR is feasible in selected adult Ph+ ALL patients. Of further relevance, TKI re-challenge was successful in 3/5 patients who relapsed, similarly to what observed in CML.

Cardiological parameters predict mortality and cardiotoxicity in oncological patients.

Oncological patients suspected at risk for cardiotoxicity are recommended to undergo intensified cardiological surveillance. We investigated the value of cardiac biomarkers and patient-related risk factors [age, cardiovascular risk factors (CVRFs), and cardiac function] for the prediction of all-cause mortality (ACM) and the development of cardiotoxicity. Between January 2016 and December 2020, patients with oncological diseases admitted to the Cardio-Oncology Unit at the Heidelberg University Hospital were included. They were evaluated by medical history, physical examination, 12-lead electrocardiogram, 2D echocardiography, and cardiac biomarkers [high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP)]. The primary endpoint was defined as ACM and the secondary endpoint was defined as cardiotoxicity, as defined by the European Society of Cardiology. Of the 1971 patients enrolled, the primary endpoint was reached by 490 patients (25.7%) with a median of 363.5 [interquartile range (IQR) 121.8, 522.5] days after presentation. Hs-cTnT of ≥ 7ng/L [odds ratio (OR) 1.82, P<0.001] and NT-proBNP (OR 1.98, P<0.001) were independent predictors of ACM, while reduced left ventricular ejection fraction was not associated with increased ACM (P=0.85). The secondary endpoint was reached by 182 patients (9.2%) with a median of 793.5 [IQR 411.2, 1165.0] days. Patients with multiple CVRFs (defined as high risk, n=886) had an increased risk of cardiotoxicity (n=100/886, 11.3%; hazard ratio 1.57, P=0.004). They showed elevated baseline values of hs-cTnT (OR 1.60, P=0.006) and NT-proBNP (OR 4.00, P<0.001) and had an increased risk of ACM (OR 1.43, P=0.031). In cancer patients, CVRF accumulation predicts cardiotoxicity whereas elevated hs-cTnT or NT-proBNP levels are associated with ACM. Accordingly, less intensive surveillance protocols may be warranted in patients with low cardiac biomarker levels and absence of CVRFs.

Addressing Attrition from Psychotherapy for PTSD in the U.S. Department of Veterans Affairs

The United States Department of Veterans Affairs (VA) uses a systematized approach for disseminating evidence-based, trauma-focused psychotherapies for post-traumatic stress disorder (PTSD). Within this approach, veterans with PTSD must often choose between Prolonged Exposure (PE) and Cognitive Processing Therapy (CPT), each delivered in their standard protocols. Many veterans have been greatly helped by this approach. Yet limiting trauma-focused therapy to these two options leaves the VA unable to fully address the needs of a variety of veterans. This limitation, among other factors, contributes to the suboptimal attrition rates within the VA. The present review proposes solutions to address treatment barriers that are both practical (such as time and travel constraints) and psychological (such as resistance to trauma exposure). By reducing barriers, attrition may lessen. Proposed countermeasures against practical barriers include intensive protocols, shortened sessions, telehealth, smartphone application delivery, or any combination of these methods. Countermeasures against psychological barriers include alternative evidence-based treatment programs (such as Acceptance and Commitment Therapy), intensive protocols for exposure-based treatments, and the integration of components from complementary treatments to facilitate PE and CPT (such as Motivational Interviewing or family therapy). By further tailoring treatment to veterans’ diverse needs, these additions may reduce attrition in VA services for PTSD.

In-Depth Immune Profiling in Children with BCP-ALL within the AIEOP-BFM ALL 2017 Study

The international multicenter frontline therapy trial AIEOP-BFM ALL 2017 prospectively randomizes CD19-targeting T-cell engager blinatumomab (BLN) against standard of care (SOC) to improve outcomes in pediatric patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) stratified for high (HR) and medium (MR) risks of relapse. In HR arm BLN is given earlier, directly after intensified HR therapy block, while in the MR arm, it is given towards the end of chemotherapy, before maintenance. The immune composition prior to BLN might thus differ between both treatment groups (HR vs MR) which may impact BLN-mediated anti-leukemic activity. Within the Germany-wide immune monitoring program accompanying the AIEOP-BFM ALL 2017 trial we addressed this question and studied a total of 1056 longitudinal peripheral blood samples collected between 11/2018 and 05/2022 from 381 BCP-ALL pts. Samples were prospectively analyzed with multicolor flow cytometry to study immune cell composition (Panel 1) at the time of BLN application (d0) and under ongoing immunotherapy within first 24h (d1), at day 14 (d14), at the end of the cycle I (d28) and end of cycle 2 (day28_II), if applicable (Figure 1A). In-depth T-cell profiling was performed in the BLN arm, utilizing 4 additional 12-color panels concentrated on markers associated with T-cell functionality (measured with standardized cytometer settings). Data were analyzed using classical 2D-manual gating strategies (&amp;gt; 2000 variables) and completed with R-based machine learning algorithms; namely partial Least-Squares Discriminant Analysis (PLS-DA), a multivariate dimensionality-reduction tool for identifying HR- and MR-defining immune signatures and PhenoGraph algorithm for unsupervised T-cell cluster detection. T-cell receptor excision circles (TRECs) and TR-repertoire analysis were also performed among paired samples of 117 BLN-treated pts. Baseline immune composition differed notably between HR and MR pts directly prior to BLN therapy, as shown by PLS-DA analysis on manually gated immune subsets. HR pts showed higher neutrophil counts and lower lymphocyte and monocyte counts compared to MR pts. Interestingly, MR pts had higher levels of B- and T-cells, which are crucial for BLN-mediated T-cell activation. HR pts displayed an elevated CD4+/CD8+ ratio, shifted naïve/memory T-cell phenotypes and increased proportions of immunosuppressive T-regulatory cells. These results suggest that more intensive therapy protocols directly prior to BLN influence the immune composition towards compromised states in the HR arm, potentially affecting BLN-mediated T-cell leukemia control. BLN effectively depleted CD19+ cells in 221 out of 224 pts. We observed significantly stronger T-cell activation/expansion in MR pts compared to HR pts under BLN therapy. This expansion that was primarily attributed to naïve CD8+ T-cell populations, resulting from clonal T-cell proliferation independent of thymic contribution, as supported by TREC and TR-repertoire analysis. The PhenoGraph clustering also identified this expanding naïve CD8+ T-cell populations, surprisingly marked by loss of adhesion molecule DNAM1 (panel 1), normally involved in NK and T-cell mediated cytotoxicity and by gaining the expression of TIM-3 (panel 3), an inhibitory molecule usually co-expressed with PD1 on exhausted T-cells with memory phenotypes. In this setting however, TIM3 was not co-expressed with PD1 (Figure 1B) and its expression was correlated with the B-cell levels at baseline and was strongest in MR pts under BLN therapy. Our data suggest an until now undescribed association between DNAM1 and TIM3 with BLN-mediated T-cell activation, hinting that they may serve as a measure of T-cell activation strength or an early T-cell exhaustion marker. In conclusion our study provides clinically relevant insights in how chemotherapy prior BLN might affect the patients´ immune system, possibly influencing the BLN anti-leukemic activity, and helps to determine the optimal place of immunotherapy with BLN in multimodal treatment schedules. Here, we report until know undescribed effect of BLN on T-cell compartment. Upcoming clinical data, which will be correlated with obtained immune profiles will answer the open question regarding the clinical relevance of these findings, and shed light into the mechanisms determining response to BLN, for its maximum benefit in childhood ALL.

Neurophysiological underpinnings of an intensive protocol for upper limb motor recovery in subacute and chronic stroke patients.

Upper limb (UL) motor impairment following stroke is a leading cause of functional limitations in activities of daily living. Robot-assisted therapy supports rehabilitation, but how its efficacy and the underlying neural mechanisms depend on the time after stroke is yet to be assessed. We investigated the response to an intensive protocol of robot-assisted rehabilitation in sub-acute and chronic stroke patients, by analyzing the underlying changes in clinical scores, electroencephalography (EEG) and end-effector kinematics. We aimed at identifying neural correlates of the participants' upper limb motor function recovery, following an intensive 2-week rehabilitation protocol. Prospective cohort study. Inpatients and outpatients from the Neurorehabilitation Unit of Pisa University Hospital, Italy. Sub-acute and chronic stroke survivors. Thirty-one stroke survivors (14 sub-acute, 17 chronic) with mild-to-moderate UL paresis were enrolled. All participants underwent ten rehabilitative sessions of task-oriented exercises with a planar end-effector robotic device. All patients were evaluated with the Fugl-Meyer Assessment Scale and the Wolf Motor Function Test, at recruitment (T0), end-of-treatment (T1), and one-month follow-up (T2). Along with clinical scales, kinematic parameters and quantitative EEG were collected for each patient. Kinematics metrics were related to velocity, acceleration and smoothness of the movement. Relative power in four frequency bands was extracted from the EEG signals. The evolution over time of kinematic and EEG features was analyzed, in correlation with motor recovery. Both groups displayed significant gains in motility after treatment. Sub-acute patients displayed more pronounced clinical improvements, significant changes in kinematic parameters, and a larger increase in Beta-band in the motor area of the affected hemisphere. In both groups these improvements were associated to a decrease in the Delta-band of both hemispheres. Improvements were retained at T2. The intensive two-week rehabilitation protocol was effective in both chronic and sub-acute patients, and improvements in the two groups shared similar dynamics. However, stronger cortical and behavioral changes were observed in sub-acute patients suggesting different reorganizational patterns. This study paves the way to personalized approaches to UL motor rehabilitation after stroke, as highlighted by different neurophysiological modifications following recovery in subacute and chronic stroke patients.

Intensive cognitive behavioral group therapy for the treatment of panic disorder

Panic disorder is one of the most commonly occurring emotional disorder, showing increased prevalence rates since the COVID-19 pandemic. The ever-growing number of patients in need of treatment is a heavy burden on the healthcare system, which draws attention to the importance of low-intensity, short and effective psychological interventions in the treatment of mental disorders, especially in the field of primary care. According to international guidelines, the recommended evidence-based treatment of panic disorder is cognitive behavioral therapy, which is based on the cognitive model of panic disorder. According to the model, a panic attack develops in those who catastrophize the symptoms of the normal stress reaction, i.e., consider them a sign of a serious physical illness such as heart-attack and react to this with intense anxiety. Based on Salkovskis and Clark (1986), we developed a 5 session, intensive cognitive behavioral group therapy protocol for panic patients. Effectiveness of the short group therapy was assessed with questionnaires (Spielberger's State-Trait Anxiety Inventory, Beck Depression Inventory) and an additional subjective scale. Paired sample t-tests were conducted. Our results suggest that the intensity of anxiety and depressive symptoms (t(36) = 5.497, p<0.0001; Z = -4.871, p<0.0001) as well as the frequency of panic attacks (Z= -5.190, p<0.0001) decreased significantly after the 5 session group therapy. Our clinical study provides further evidence by the effectiveness of low-intensity psychological interventions, offering an evidence-based protocol for professionals working in primary as well as mental health care. Orv Hetil. 2023; 164(42): 1665-1672.

Early Cancer Detection in Li-Fraumeni Syndrome with Cell-Free DNA.

By utilizing an integrated cell-free DNA approach, liquid biopsy shows earlier detection of cancer in patients with LFS compared with current clinical surveillance methods such as imaging. Liquid biopsy provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients. See related commentary by Latham et al., p. 23. This article is featured in Selected Articles from This Issue, p. 5.

An Exploration of the Effectiveness of Different Intensity Protocols of Modified Constraint-Induced Therapy in Stroke: A Systematic Review.

To examine the effectiveness of different modified Constraint-Inuced Therapy (mCIMT) protocol intensities on upper extremity motor function in adults with hemiplegia. A search was conducted in PubMed, Scopus, EBSCO, and Cochrane Library for articles published between April 2010 and December 2021. Only randomized controlled trials (RCTs) were included. Studies were excluded if they used a sample of less than five, mCIMT in combination with other therapy, and/or if they were not written in English. Methodologic quality was assessed using the Cochrane collaboration risk of bias tool-2. Thirty-six RCTs with a total of 721 participants were included. Most researchers followed a moderate to low protocol intensity in terms of total treatment time and moderate to high intensity with regard to restriction time. Almost all of the upper limb motor function measures showed statistically significant improvements (p < .05) after mCIMT, irrespective of the protocol's intensity, but there was lack of high-quality studies. Statistically significant improvements did not always translate to clinical importance. Low-intensity CIMT protocols may result in comparable improvements to more intensive ones but caution has to be taken when drawing conclusions due to high risk of bias studies.

Initial Experiences in Adolescents and Young Adults with T-Cell Acute Lymphoblastic Leukemia/Lymphoma Treated with the Modified BFM 2002 Protocol in a Resource-Constrained Setting

T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) in adolescents and young adults (AYAs) is a clinically aggressive malignancy and life-threatening at diagnosis. Intensive chemotherapy protocols, inspired by the Berlin-Frankfurt-Münster (BFM) regimen, along with central nervous system (CNS) prophylaxis, have achieved a 75 to 85% 5-year disease-free survival rate. However, in cases of marrow and CNS relapses, second-line chemotherapy is usually ineffective. This study aimed to assess the safety and efficacy of the BFM 2002 protocol and to correlate clinical profiles and prognostic factors with survival outcomes in AYA T-ALL/LBL patients. We retrospectively analyzed data from T-ALL/LBL patients treated at the Department of Medical Oncology, Sri Aurobindo Institute of Medical Sciences (SAIMS), Indore, between 2018 and 2021. Twenty-one patients aged 15 to 29 years were studied for their clinical course and laboratory parameters over 36 months. Diagnosis and risk stratification were performed following the guidelines of the BFM 2002 protocol. All patients received treatment and monitoring according to this pediatric-inspired protocol. The median age of the patients was 17 years (range: 15–28 years). Eleven patients presented with mediastinal lymph node enlargement, 10% exhibited CNS involvement, and none had testicular involvement. Eleven patients had marrow blasts greater than 25%, indicative of acute lymphoblastic leukemia. All 21 patients were treated according to the intensive modified BFM 2002 protocol and achieved morphological remission after a median follow-up of 24 months (range: 18–36 months). Seventeen patients achieved minimal residual disease (MRD) negativity post-induction. MRD at day 33 showed a significant association with the probability of disease relapse (p = 0.0015). There were five deaths (24%), one due to toxicity and four due to relapse. The study recorded an 18-month overall survival of 76%. These results were achieved despite financial constraints. Data were entered into a spreadsheet, and statistical analysis was performed using IBM SPSS version 23. Continuous data are presented as ranges and medians, while categorical variables are shown as percentages and numbers. A chi-squared test for association, with a significance level set at p &lt; 0.05, was conducted as indicated. AYA T-ALL/LBL requires intensive treatment regimens. With biological characterization of LBL/ALL and close therapy monitoring, encouraging outcomes can be achieved even in resource-limited settings.

Étude nationale française du profil des patients hospitalisés en unité pour malades difficiles

The ten French psychiatry high security care units (Unité pour Malades Difficiles : UMD) are the only forensic institutions in the country to provide care for dangerous and/or difficult patients (homicide, acts of barbarity, sexual assault, cannibalism, pyromania…). They benefit from intensive care protocols and high security measures. In this first epidemiological multicentric descriptive study in French history including 418 violent and homicidal patients, medico-judiciary and social characteristics of the standard UMD patient are described. This standard patient is a young single man, with a criminal record and from an underprivileged background, suffering from treatment-resistant schizophrenia with strong delusional symptoms. He has a weak compliance to treatment, low insight, a history of drug abuse and is admitted for severe violence against others and in particular against caretakers or for homicidal act. The study's secondary goal is to revisit the risk factors of high violence described in medical literature and to reveal new ones (cultural uprooting, parental psychopathology, homelessness, perverse sadistic behavior, aggressive behavior a month prior the violent acting out, resistance to antipsychotic drugs, treatment discontinuation), particularly in the homicidal patient cohort. This study should enable clinicians to evaluate dangerousness and to offer better medical care and preventive measures against violence.

Recreationally Active Adults Exhibit Overtraining Following An Intensive 3-Week Lab-Controlled Training Protocol

Recreationally Active Adults Exhibit Overtraining Following An Intensive 3-Week Lab-Controlled Training Protocol

Randomised, open-label, non-inferiority clinical trial on the efficacy and safety of a 7-day vs 14-day course of antibiotic treatment for uncomplicated enterococcal bacteraemia: the INTENSE trial protocol

IntroductionEnterococcus spp is responsible for 8%–15% of total bacteraemias with an associated global mortality around 23%–30%. Regarding the clinical management of enterococcal bacteraemia, the evidence on the duration of antibiotic...

Implementasi Kebijakan New Normal pada Pelaku Usaha Waterpark Transera di Kabupaten Bekasi

The purpose of this study was to conclude that the management of the waterpark Bekasi supported it completely and ignored the agnation of new normal policies, Management understands the importance of applying health protocols to businesses and individuals so that the waterpark begins implementing strict, intensive health protocols starting with all of waterpark Bekasi, as well as the transfer of tools and the resulting infrastructure of the covid-19 pandemic. Causing various policies to break the spread of the covid-19 virus in Indonesia. Efforts by governments are among those that are implemented Civility to society in order to carry out Covid-19, excluding activities in all forms of crowds, assemblies, and avoiding meetings involving many people. Such efforts are aimed at communities that can be done to break the current covid-19 pandemic chain. The provisions of infrastructure in accordance with government regulations and therefore Transera waterpark provide comfort and security to the organizers.

Effects of intensive rehabilitation on functioning in patients with mild and moderate Charcot-Marie-Tooth disease: a real-practice retrospective study.

Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies and can lead to progressive muscular weakness, pes cavus, loss of deep tendon reflexes, distal sensory loss, and gait impairment. There are still no effective drugs or surgical therapies for CMT, and supportive treatment is limited to rehabilitative therapy and surgical treatment of skeletal deformities. Many rehabilitative therapeutic approaches have been proposed, but timing and cadence of rehabilitative intervention are not clearly defined, and long-term follow-up is lacking in literature. The aim of this real-practice retrospective study was to assess the effectiveness of an intensive neurorehabilitation protocol on muscle strength and functioning in CMT patients. We analyzed data of patients with diagnosis of mild to moderate CMT. The rehabilitation program lasted 2-4 h a day, 5 days a week, for 3 weeks and consisted of manual treatments, strengthening exercises, stretching, core stability, balance and resistance training, aerobic exercises, and tailored self-care training. Data were collected at baseline (T0), after treatment (T1), and at the 12-month mark (T2) in terms of the following outcome measures: muscle strength, pain, fatigue, cramps, balance, walking speed, and ability. We included 37 CMT patients with a median age of 50.72 ± 13.31 years, with different forms: demyelinating (n = 28), axonal (n = 8), and mixed (n = 1). After intensive rehabilitation treatment, all outcomes significantly improved. This improvement was lost at the 1-year mark. Taken together, these findings suggest that an intensive rehabilitation program improves short-term symptoms and functional outcomes in a cohort of inpatients affected by mild to moderate CMT.

Treating relapsed B cell-precursor ALL in children with a setting-adapted mitoxantrone-based intensive chemotherapy protocol (TMH rALL-18 PROTOCOL) - experience from Tata Memorial Hospital, India.

The outlook of relapsed ALL in low- and middle-income countries (LMICs) is dismal due to high treatment-related toxicities and inadequate resources. We report our experience of using a locally adapted mitoxantrone-based protocol for non-high risk (HR) relapsed B-ALL (rALL). A retrospective cum prospective study of standard and intermediate risk (SR and IR) rALL patients treated on TMH rALL-18 protocol (adapted from COG/UKALLR3/Int-Re-ALL protocols) between November 2018 and January 2021 was analyzed. The protocol comprising of 7 blocks of multi-agent chemotherapy including mitoxantrone in induction followed by local irradiation and maintenance, underwent serial modifications based on our experience with initial patients. Eighty-two patients (SR rALL, 3; IR rALL, 79) were treated on TMH rALL-18 protocol. Of 321 grade 3/4 reported toxicities, around 43% (138 toxicities) were noted during induction. Induction chemotherapy was outpatient-based; however, 68 patients (82.9%) required supportive care admissions. Twelve out of 19 patients with gram negative bacilli sepsis (included 7 MDRO) died during reinduction. Five remission deaths were seen during block 3 after which cytarabine was dose reduced (3g to 2g/m2). Post-reinduction minimal residual disease was negative in 54 (80.6%) out of 67 evaluable patients. At a median follow-up of 24months (95% CI 22-27), the estimated 2-year event-free and overall survival of the entire cohort was 58% (95% CI 48.1-69.9) and 60.3% (95% CI 50.5-72). Until the time, targeted therapies are freely accessiblein LMICs, strengthening supportive careas well as local adaptation of protocols that strike a fine balance between efficacy and tolerability are mandated.

Early occupational therapy in mechanically ventilated patients improves functional status: Study protocol

Background: Experts suggest implementing measures that include analgesia, sedation, delirium prevention and early mobilization (ASDM) in patients undergoing mechanical ventilation (MV) to reduce complications. However, there is limited evidence of occupational therapy in these patients. The aim of the research is to compare functional independence in patients undergoing MV of an intensive and early occupational therapy protocol versus to standard ASDM strategy. Method/Design: A prospective, multicenter, randomized clinical trial, with parallel groups (control and intervention groups). Participants will be hospitalized patients, over 18 years of age, admitted to the intensive care unit (ICU) and with the need of invasive MV. The intervention group will receive two daily 30-minute sessions of occupational therapy for 10 days. This study will research the effect of occupational therapy on functional independence, motor and cognitive status, evaluating at days 28 and 90. Discussion: This work contributes to the theoretical and practical work of occupational therapists who work in the ICU. The implementation of protocols of occupational therapy in mechanically ventilated patients can contribute to the independence and functionality of patients. Conclusion: Our research aims to contribute to the generation of systematized, organized, and feasible protocols that can be implemented in ICU. Trial Registration: ClinicalTrials.gov NCT04819529

Intensive neurorehabilitation and allogeneic stem cells transplantation in canine degenerative myelopathy.

Degenerative myelopathy (DM) is a neurodegenerative spinal cord disease with upper motor neurons, with progressive and chronic clinical signs, similar to amyotrophic lateral sclerosis (ALS). DM has a complex etiology mainly associated with SOD1 gene mutation and its toxic role, with no specific treatment. Daily intensive rehabilitation showed survival time near 8 months but most animals are euthanized 6-12 months after clinical signs onset. This prospective controlled blinded cohort clinical study aims to evaluate the neural regeneration response ability of DM dogs subjected to an intensive neurorehabilitation protocol with mesenchymal stem cells (MSCs) transplantation. In total, 13 non-ambulatory (OFS 6 or 8) dogs with homozygous genotype DM/DM and diagnosed by exclusion were included. All were allocated to the intensive neurorehabilitation with MSCs protocol (INSCP) group (n = 8) or to the ambulatory rehabilitation protocol (ARP) group (n = 5), which differ in regard to training intensity, modalities frequency, and MSCs transplantation. The INSCP group was hospitalized for 1 month (T0 to T1), followed by MSCs transplantation (T1) and a second month (T2), whereas the ARP group was under ambulatory treatment for the same 2 months. Survival mean time of total population was 375 days, with 438 days for the INSCP group and 274 for the ARP group, with a marked difference on the Kaplan-Meier survival analysis. When comparing the literature's results, there was also a clear difference in the one-sample t-test (p = 0.013) with an increase in time of approximately 70%. OFS classifications between groups at each time point were significantly different (p = 0.008) by the one-way ANOVA and the independent sample t-test. This INSCP showed to be safe, feasible, and a possibility for a long progression of DM dogs with quality of life and functional improvement. This study should be continued.

Social buffering reduces fear expression in Wistar rats when tested in pairs, but not when retested alone

Social buffering is a phenomenon in which the stress response of an individual can be reduced by the presence of another individual. However, little is known about the effect of social buffering on aversive after memory extinction, especially when animals are tested alone afterwards. The aim of this study was to verify the social buffering effect in rats during the extinction session of the contextual fear conditioning model and the fear response when animals are tested alone in the following day. Animals were divided into subjects and associates, with the subjects undergoing the fear conditioning protocol and the associates paired with the subjects during the fear extinction session. Across five different experiments, we tested moderate and high intensity contextual fear conditioning protocols, as well four variations of pairs: (i) two conditioned subjects, (ii) a conditioned subject and a non-conditioned associate, (iii) a conditioned subject and an associate who observed the conditioning of the partner and (iv) two conditioned subjects, with one treated with diazepam. The social buffering effect was found efficient to reduce the fear memory expression during the fear extinction session. In the moderate intensity protocol, the reduction in freezing time occurred only in subjects accompanied by non-conditioned associates and observer associates. In the high intensity protocol, the social buffering effect occurred in subjects accompanied by either conditioned or non-conditioned associates, although the effect was more evident in the presence of non-conditioned subjects. Treatment of the conditioned associates with diazepam did not improve the social buffering effect. Moreover, social buffering effects were not correlated with self-grooming or prosocial behaviors, which indicates that the presence of another animal might decrease freezing by promotion of exploratory activity. Finally, the social buffering effect was not observed in the extinction test, either because the extinction was too effective in the moderate intensity protocol or because the extinction was equally ineffective in the high intensity protocol. Our results suggest that social buffering does not improve fear extinction consolidation.